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Quantitative interaction proteomics of neurodegenerative disease proteins

Hosp, Fabian, Vossfeldt, Hannes, Heinig, Matthias, Vasiljevic, Djordje, Arumughan, Anup, Wyler, Emanuel, Landthaler, Markus, Hubner, Norbert, Wanker, Erich E., Lannfelt, Lars, Ingelsson, Martin, Lalowski, Maciej, Voigt, Aaron, Selbach, Matthias, Owen, Michael John, O'Donovan, Michael Conlon, Escott-Price, Valentina, Holmans, Peter Alan, Williams, Julie and Hamshere, Marian L. 2015. Quantitative interaction proteomics of neurodegenerative disease proteins. Cell Reports 11 (7) , pp. 1134-46. 10.1016/j.celrep.2015.04.030

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Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer's disease (AD), Huntingtin (HTT) for Huntington's disease, Parkin (PARK2) for Parkinson's disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of A

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Publisher: Cell Press
ISSN: 2211-1247
Last Modified: 13 Apr 2019 02:58

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